Optically active 2-allylcarboxylic acid derivative and process for producing the same

ABSTRACT

The present invention provides a process for producing an optically active 2-allylcarboxylic acid derivative, which is useful as a pharmaceutical intermediate, from readily available and inexpensive starting materials by the process which can be practiced on a commercial scale in a simple and easy manner, and certain 2-allylcarboxamide derivatives, which are novel and important intermediates in that process. An N-allylcarboxamide derivative undergoes rearrangement reaction diastereoselectively in the presence of a base to give a 2-allylcarboxamide derivative, the resulting derivative is subjected to a carbamation reaction and solvolysis to give an optically active 2-allylcarboxylic acid ester, and then the ester obtained is stereoselectively hydrolyzed using an enzyme to produce 2-allylcarboxylic acid having a high optical purity. In addition, the present invention provides a 2-allylcarboxamide derivative compound which is a novel intermediate in the process of the present invention.

TECHNICAL FIELD

The present invention relates to a novel intermediate compound, namely a2-allylcarboxamide derivative, and to a process for producing anoptically active 2-allylcarboxylic acid derivative utilizing suchintermediate. For example, an optically active 2-allyloctanoic acidproducible in accordance with the present invention is known to serve asan intermediate in the production of astrocyte function improvers(Japanese Kokai Publication Hei-07-316092).

BACKGROUND ART

Known in the art for the production of an optically active2-allyloctanoic acid are 1) the process comprising reacting anoctanamide compound of camphorsultam, which is an optically activecompound, with diisopropyllithium amide, then reacting the product withan allyl halide to introduce an allyl group diastereoselectively intothe octanamide moiety at the position 2 thereof, and eliminating theauxiliary camphorsultam group using a peracid or, alternatively,introducing a propargyl group in lieu of the above-mentioned allylgroup, followed by reduction thereof to an allyl group (WO 99/58513),and 2) the process comprising optically resolving racemicpropynyloctanoic acid by fractional crystallization using opticallyactive phenethylamine and reducing the thus-obtained optical isomer(Japanese Kokai Publication Hei-08-291106), among others.

However, there are a number of problems in putting the above-mentionedprocess (1) into practice on a commercial scale; for example,camphorsultam, which is a very expensive chiral auxiliary group, isrequired, the allylation or propalgylation reaction is to be carried outat a very low temperature of −78° C., and hydrogen peroxide is requiredto eliminate the auxiliary camphorsultam group. As for the prior artprocess (2), the optical resolution efficiency is low and, for obtaining2-propynyloctanoic acid having a sufficiently high optical purity foruse as an pharmaceutical intermediate, in particular, a plurality ofrepetitions of fractional crystallization are required, which inevitablyresults in a reduction in yield.

SUMMARY OF THE INVENTION

In view of the above-discussed problems with the prior art processes,the present inventors made intensive investigations in an attempt todevelop a process capable of being carried out safely even on a largescale using only those starting materials or reagents which can behandled with ease on an industrial scale and are inexpensive and readilyavailable. As a result, they have developed a process for producing andobtaining 2-allylcarboxylic acids having a high optical purity withgreat efficiency via novel and important intermediates, namely2-allylcarboxamide compounds by utilizing very inexpensive opticallyactive sources as asymmetric auxiliary groups, stereoselectivelyallylating carboxylic acids at the position 2 thereof without utilizingany very low temperature reaction, realizing protective groupelimination very efficiently and, further, utilizing an enzymaticreaction.

Thus, the present invention provides

a process for producing an optically active 2-allylcarboxylic acidrepresented by the following formula (5);

wherein R⁴represents a substituted or unsubstituted alkyl groupcontaining 1 to 18 carbon atoms, a substituted or unsubstituted arylgroup containing 6 to 20 carbon atoms or a substituted or unsubstitutedaralkyl group containing 7 to 20 carbon atoms and *2 indicates that thecarbon atom marked therewith is an asymmetric carbon atom;,

which comprises:

-   (a) reacting a carboxamide compound represented by the following    formula (2);    wherein R¹, R² and R⁴ each independently represents a substituted or    unsubstituted alkyl group containing 1 to 18 carbon atoms, a    substituted or unsubstituted aryl group containing 6 to 20 carbon    atoms or a substituted or unsubstituted aralkyl group containing 7    to 20 carbon atoms and *1 indicates that the carbon atom marked    therewith is an asymmetric carbon atom;    with an organometallic compound and then further with a compound    represented by the formula;    ClCOOR⁵    wherein R⁵ represents a substituted or unsubstituted alkyl group    containing 1 to 18 carbon atoms, a substituted or unsubstituted aryl    group containing 6 to 20 carbon atoms or a substituted or    unsubstituted aralkyl group containing 7 to 20 carbon atoms; to give    a 2-allylcarboxamide derivative represented by the following formula    (3);    wherein R¹, R², R⁴, R⁵, *1 and *2 are as defined above;,-   (b) reacting the derivative (3) with a compound represented by the    formula MOR6    wherein M represents an alkali metal and R⁶ represents a substituted    or unsubstituted alkyl group containing 1 to 20 carbon atoms    to give a 2-allylcarboxylic acid ester derivative represented by the    following formula (4);    wherein R⁴, R⁶ and *2 are as defined above;, and-   (c) further hydrolyzing the derivative (4).

The invention also provides

a process for producing a 2-allylcarboxamide derivative represented bythe following formula (6);

wherein R¹, R², R⁴ and *1 are as defined above and *2 indicates that thecarbon atom marked therewith is an asymmetric carbon atom;,

which comprises reacting a carboxamide compound represented by theformula (2) given above with an organometallic compound.

The invention also provides

a process for producing a 2-allylcarboxamide derivative represented bythe formula (3) given above,

which comprises reacting a compound represented by the formula (6) givenabove in the presence of a base and further with a compound representedby the formula;ClCOOR⁵wherein R⁵ is as defined above.

The invention further provides

a process for producing a 2-allylcarboxamide derivative represented bythe formula (3) given above,

which comprises reacting a carboxamide compound represented by theformula (2) given above with an organometallic compound and further witha compound represented by the formula;ClCOOR⁵wherein R⁵ is as defined above.

The invention further provides

a process for producing a 2-allylcarboxylic acid represented by thefollowing formula (8);

wherein R⁴is as defined hereinabove, R⁹ represents a hydrogen atom or asubstituted or unsubstituted alkyl group containing 1 to 20 carbonatoms, and * indicates that the carbon atom marked therewith is anasymmetric carbon atomor an ester derivative thereof;,

which comprises reacting a 2-allylcarboxamide derivative represented bythe following formula (7);

wherein R⁴ is as defined hereinabove, R⁷ and R⁸ each represents asubstituted or unsubstituted alkyl group containing 1 to 18 carbonatoms, a substituted or unsubstituted aryl group containing 6 to 20carbon atoms or a substituted or unsubstituted aralkyl group containing7 to 20 carbon atoms and R⁷ and R⁸ may be bound together to form a ring,X represents C, S or S(O), Y represents CH, O or NH and * is as definedhereinabove;with a compound represented by the formula MOR⁹ wherein M represents analkali metal and R⁹ is as defined hereinabove and,

if necessary, hydrolyzing the resulting ester.

The invention still further provides

a process for producing an optically active 2-allylcarboxylic acidrepresented by the formula (5) given above,

which comprises causing an enzyme source having asymmetric hydrolysisactivity to act on a 2-allylcarboxylic acid ester derivative representedby the formula (4) given above and

collecting the resulting optically active 2-allylcarboxylic acid.

Furthermore, the invention provides

a process for producing an optically active 2-allylcarboxylic acid esterrepresented by the formula (4) given above,

which comprises causing an enzyme source having asymmetric hydrolysisactivity to act on a 2-allylcarboxylic acid ester derivative representedby the formula (4) given above and

collecting the unreacted optically active 2-allylcarboxylic acid ester.

Finally, the invention relates to

a 2-allylcarboxamide derivative compound represented by the followingformula (1);

wherein R¹, R², R³, R⁴, *1 and *2 are as defined above.

DETAILED DESCRIPTION OF THE INVENTION

In the following, the invention is described in detail.

First, the 2-allylcarboxamide derivative compound represented by theformula (1) is described.

In the formula, R¹ and R² each independently represents an alkyl group,aryl group or aralkyl group. The alkyl group is a substituted orunsubstituted one containing 1 to 18 (preferably 1 to 10, morepreferably 1 to 6) carbon atoms, such as, for example, methyl group,ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutylgroup, sec-butyl group, tert-butyl group, n-pentyl group, isopentylgroup or n-hexyl group.

The aryl group is a substituted or unsubstituted one containing 6 to 20(preferably 6 to 10) carbon atoms, such as, for example, phenyl group,1-naphthyl group, 2-naphthyl group, 4-methylphenyl group, 3-methylphenylgroup, 2-methylphenyl group, 4-ethylphenyl group, 3-ethylphenyl group,4-methoxyphenyl group, 3-methoxyphenyl group, 2-methoxyphenyl group,4-nitrophenyl group, 4-phenylphenyl group, 4-chlorophenyl group or4-bromophenyl group.

The aralkyl group is a substituted or unsubstituted one containing 7 to20 (preferably 7 to 10) carbon atoms, such as, for example, benzylgroup, 4-methylbenzyl group, 3-methylbenzyl group, 2-methylbenzyl group,4-methoxybenzyl group, 3-methoxybenzyl group, 2-methoxybenzyl group,1-phenylethyl group, 2-phenylethyl group, 1-(4-methylphenyl)ethyl group,1-(4-methoxyphenyl)ethyl group, 3-phenylpropyl group or 2-phenylpropylgroup.

Preferred as R¹ is a substituted or unsubstituted aryl group containing6 to 20 carbon atoms. In particular, phenyl group, 4-methylphenyl group,4-methoxyphenyl group, 3-methoxyphenyl group, 4-nitrophenyl group,4-chlorophenyl group, 4-bromophenyl group, 1-naphthyl group and2-naphthyl group are preferred. Preferred as R² is a substituted orunsubstituted alkyl group containing 1 to 18 carbon atoms and, inparticular, methyl group is preferred.

The combination of R¹ and R² may be that of any two substituentsarbitrarily selected from among those specifically enumeratedhereinabove. Preferred are the combination of an aryl group as R¹ and analkyl group as R² and the combination of an aryl group as R¹ and anaralkyl group as R². More preferred are the combination of phenyl group,4-methylphenyl group, 1-naphthyl group, 2-naphthyl group,4-methoxyphenyl group, 3-methoxyphenyl group, 4-nitrophenyl group,4-chlorophenyl group or 4-bromophenyl group as R¹ and methyl group as R²and the combination of phenyl group as R and 4-methylbenzyl group as R².More preferred is the combination of phenyl group as R¹ and methyl groupas R².

In the relevant formula, R⁴ represents an alkyl group, aryl group oraralkyl group. The alkyl group is a substituted or unsubstituted onecontaining 1 to 18 (preferably 1 to 10, more preferably 1 to 6) carbonatoms, such as, for example, methyl group, ethyl group, n-propyl group,isopropyl group, n-butyl group, isobutyl group, sec-butyl group,tert-butyl group, n-pentyl group, isopentyl group or n-hexyl group.

The aryl group is a substituted or unsubstituted one containing 6 to 20(preferably 6 to 10) carbon atoms, such as, for example, phenyl group,1-naphthyl group, 2-naphthyl group, 4-methylphenyl group, 3-methylphenylgroup, 2-methylphenyl group, 4-ethylphenyl group, 3-ethylphenyl group,4-methoxyphenyl group, 3-methoxyphenyl group, 2-methoxyphenyl group,4-nitrophenyl group, 4-phenylphenyl group, 4-chlorophenyl group or4-bromophenyl group.

The aralkyl group is a substituted or unsubstituted one containing 7 to20 (preferably 7 to 10) carbon atoms, such as, for example, benzylgroup, 4-methylbenzyl group, 3-methylbenzyl group, 2-methylbenzyl group,4-methoxybenzyl group, 3-methoxybenzyl group, 2-methoxybenzyl group,2-phenylethyl group, 1-(4-methylphenyl)ethyl group,1-(4-methoxyphenyl)ethyl group, 3-phenylpropyl group or 2-phenylpropylgroup.

Among those groups, an alkyl group is preferred as R⁴, and n-hexyl groupis more preferred.

R³represents a hydrogen atom, an alkyloxycarbonyl group, anaryloxycarbonyl group or an aralkyloxycarbonyl group.

The alkyloxycarbonyl group is a substituted or unsubstituted onecontaining 2 to 20 (preferably 2 to 11, more preferably 2 to 7) carbonatoms, such as, for example, methyloxycarbonyl group, ethyloxycarbonylgroup, n-propyloxycarbonyl group, isopropyloxycarbonyl group,n-butyloxycarbonyl group, isobutyloxycarbonyl group,sec-butyloxycarbonyl group, tert-butyloxycarbonyl group,n-pentyloxycarbonyl group, isopentyloxycarbonyl group orn-hexyloxycarbonyl group.

The aryloxycarbonyl group is a substituted or unsubstituted onecontaining 7 to 20 (preferably 7 to 11) carbon atoms, such as, forexample, phenyloxycarbonyl group, 1-naphthyloxycarbonyl group,2-naphthyloxycarbonyl group, 4-methylphenyloxycarbonyl group,3-methylphenyloxycarbonyl group, 2-methylphenyloxycarbonyl group,4-ethylphenyloxycarbonyl group, 3-ethylphenyloxycarbonyl group,4-methoxyphenyloxycarbonyl group, 3-methoxyphenyloxycarbonyl group,2-methoxyphenyloxycarbonyl group, 4-nitrophenyloxycarbonyl group,4-phenylphenyloxycarbonyl group, 4-chlorophenyloxycarbonyl group or4-bromophenyloxycarbonyl group.

The aralkyloxycarbonyl groups is a substituted or unsubstituted onecontaining 8 to 20 (preferably 8 to 11) carbon atoms, such as, forexample, benzyloxycarbonyl group, 4-methylbenzyloxycarbonyl group,3-methylbenzyloxycarbonyl group, 2-methylbenzyloxycarbonyl group,4-methoxybenzyloxycarbonyl group, 3-methoxybenzyloxycarbonyl group,2-methoxybenzyloxycarbonyl group, 3-phenylpropyloxycarbonyl group or2-phenylpropyloxycarbonyl group.

As preferred species, there may be mentioned a hydrogen atom,phenyloxycarbonyl group, isopropyloxycarbonyl group, isobutyloxycarbonylgroup, sec-butyloxycarbonyl group and tert-butyloxycarbonyl group. Morepreferred are a hydrogen atom, phenyloxycarbonyl group andisopropyloxycarbonyl group.

The asymmetric carbon atom marked with *1 may have either the R-formabsolute configuration or the S-form absolute configuration. Similarly,the asymmetric carbon atom marked with *2 may have either the R-formabsolute configuration or the S-form absolute configuration.

Now, the step of producing the 2-allylcarboxamide derivative of theformula (3) by reacting the carboxamide compound of the formula (2) withan organometallic compound and then with a chlorocarbonate ester of theformula ClCOOR⁵ is described.

The compound (2) to be used in this step can be prepared, for example bythe amidation reaction between the corresponding carboxylic acid halideor carboxylic anhydride and N-allylamine derivative, which are readilyavailable, or by the N-allylation reaction of the correspondingcarboxamide compound. The compound (2) to be used may be in the form ofa racemic mixture or in an optically active form. The use of anoptically active form is preferred.

In the relevant formulas, R¹ and R² each independently represents analkyl group, aryl group or aralkyl group. The alkyl group is asubstituted or unsubstituted one containing 1 to 18 (preferably 1 to 10,more preferably 1 to 6) carbon atoms, such as, for example, methylgroup, ethyl group, n-propyl group, isopropyl group, n-butyl group,isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group,isopentyl group or n-hexyl group.

The aryl group is a substituted or unsubstituted one containing 6 to 20(preferably 6 to 10) carbon atoms, such as, for example, phenyl group,1-naphthyl group, 2-naphthyl group, 4-methylphenyl group, 3-methylphenylgroup, 2-methylphenyl group, 4-ethylphenyl group, 3-ethylphenyl group,4-methoxyphenyl group, 3-methoxyphenyl group, 2-methoxyphenyl group,4-nitrophenyl group, 4-phenylphenyl group, 4-chlorophenyl group or4-bromophenyl group.

The aralkyl group is a substituted or unsubstituted one containing 7 to20 (preferably 7 to 10) carbon atoms, such as, for example, benzylgroup, 4-methylbenzyl group, 3-methylbenzyl group, 2-methylbenzyl group,4-methoxybenzyl group, 3-methoxybenzyl group, 2-methoxybenzyl group,1-phenylethyl group, 2-phenylethyl group, 1-(4-methylphenyl)ethyl group,1-(4-methoxyphenyl)ethyl group, 3-phenylpropyl group or 2-phenylpropylgroup.

Preferred as R¹ in the formula (2) is an aryl group and, in particular,phenyl group, 4-methylphenyl group, 4-methoxyphenyl group,3-methoxyphenyl group, 4-nitrophenyl group, 4-chlorophenyl group,4-bromophenyl group, 1-naphthyl group and 2-naphthyl group arepreferred.

Preferred as R² in the formula (2) are methyl group, benzyl group and4-methylbenzyl group, and methyl group and 4-methylbenzyl group are morepreferred.

The combination of R¹ and R² may be that of any two substituentsarbitrarily selected from among those specifically enumeratedhereinabove. Preferred are the combination of an aryl group as R¹ and analkyl group as R² and the combination of an aryl group as R¹ and anaralkyl group as R². More preferred are the combination of phenyl group,4-methylphenyl group, 1-naphthyl group, 2-naphthyl group,4-methoxyphenyl group, 3-methoxyphenyl group, 4-nitrophenyl group,4-chlorophenyl group or 4-bromophenyl group as R¹ and methyl group as R²and the combination of phenyl group as R¹ and 4-methylbenzyl group asR². More preferred is the combination of phenyl group as R¹ and methylgroup as R².

In the relevant formulas, R⁴ represents an alkyl group, aryl group oraralkyl group. The alkyl group is a substituted or unsubstituted onecontaining 1 to 18 (preferably 1 to 10, more preferably 1 to 6) carbonatoms, such as, for example, methyl group, ethyl group, n-propyl group,isopropyl group, n-butyl group, isobutyl group, sec-butyl group,tert-butyl group, n-pentyl group, isopentyl group or n-hexyl group.

The aryl group is a substituted or unsubstituted one containing 6 to 20(preferably 6 to 10) carbon atoms, such as, for example, phenyl group,1-naphthyl group, 2-naphthyl group, 4-methylphenyl group, 3-methylphenylgroup, 2-methylphenyl group, 4-ethylphenyl group, 3-ethylphenyl group,4-methoxyphenyl group, 3-methoxyphenyl group, 2-methoxyphenyl group,4-nitrophenyl group, 4-phenylphenyl group, 4-chlorophenyl group or4-bromophenyl group.

The aralkyl group is a substituted or unsubstituted one containing 7 to20 (preferably 7 to 10) carbon atoms, such as, for example, benzylgroup, 4-methylbenzyl group, 3-methylbenzyl group, 2-methylbenzyl group,4-methoxybenzyl group, 3-methoxybenzyl group, 2-methoxybenzyl group,2-phenylethyl group, 1-(4-methylphenyl)ethyl group,1-(4-methoxyphenyl)ethyl group, 3-phenylpropyl group or 2-phenylpropylgroup.

Among those, an alkyl group is preferred, and n-hexyl is more preferred.

The organometallic compound to be used includes organolithium compounds,organopotassium compounds and organomagnesium compounds. Organomagnesiumcompounds are preferred, tert-butylmagnesium halides are more preferred,and tert-butylmagnesium chloride is most preferred. As for the usage,the organometallic compound is to be used generally in an amount of notless than 1 mole, preferably 1.0 to 2.0 moles, more preferably 1.1 to1.3 moles, per mole of the compound of the formula (2).

In the formula ClCOOR⁵, R⁵represents an alkyl group, aryl group oraralkyl group.

The alkyl group is a substituted or unsubstituted one containing 1 to 18(preferably 1 to 10, more preferably 1 to 6) carbon atoms, such as, forexample, methyl group, ethyl group, n-propyl group, isopropyl group,n-butyl group, isobutyl group, sec-butyl group, tert-butyl group,n-pentyl group, isopentyl group or n-hexyl group.

The aryl group is a substituted or unsubstituted one containing 6 to 20(preferably 6 to 10) carbon atoms, such as, for example, phenyl group,1-naphthyl group, 2-naphthyl group, 4-methylphenyl group, 3-methylphenylgroup, 2-methylphenyl group, 4-ethylphenyl group, 3-ethylphenyl group,4-methoxyphenyl group, 3-methoxyphenyl group, 2-methoxyphenyl group,4-nitrophenyl group, 4-phenylphenyl group, 4-chlorophenyl group or4-bromophenyl group.

The aralkyl group is a substituted or unsubstituted one containing 7 to20 (preferably 7 to 10) carbon atoms, such as, for example, benzylgroup, 4-methylbenzyl group, 3-methylbenzyl group, 2-methylbenzyl group,4-methoxybenzyl group, 3-methoxybenzyl group, 2-methoxybenzyl group,3-phenylpropyl group or 2-phenylpropyl group.

Preferred as R⁵ are phenyl group, isopropyl group, isobutyl group,sec-butyl group and tert-butyl group. More preferred are phenyl groupand isopropyl group.

The usage of the chlorocarbonate compound represented by the formulaClCOOR⁵ is not particularly restricted but should be not less than 1mole per mole of the compound (2). Preferably, it is 1.0 to 5.0 molesper mole of the compound (2).

The solvent to be used in carrying out the reaction is not particularlyrestricted but may be any of those which will not adversely affect thereaction. Thus, there maybe mentioned, for example, hexane, toluene,xylene, tetrahydrofuran, diethyl ether, tert-butylmethyl ether, ethyleneglycol dimethyl ether, ethylene glycol diethyl ether, dimethylformamide(DMF), and mixtures of these. Toluene is preferred.

As for the reaction temperature, the reaction with the organometalliccompound is generally carried out at 25° C. to 100° C., preferably 60°C. to 90° C. The reaction time, which may vary depending on the reactiontemperature and the amount of the organometallic compound used, isgenerally 1 hour to 24 hours, preferably 5 hours to 10 hours.

The reaction with the chlorocarbonate ClCOOR⁵ is generally carried outat 0° C. to 100° C., preferably 10° C. to 70° C., more preferably 20° C.to 50° C. The reaction time, which may vary depending on the usage ofClCOOR⁵ and the reaction temperature, is generally 1 hour to 48 hours,preferably 5 hours to 24 hours.

The process for producing the compound (3) from the compound (2) can becarried out continuously, as mentioned above. If necessary, however, thereactions may be carried out each independently. Thus, it is possible toderive the compound of the formula (6) from the compound of the formula(2) by reaction with the organometallic compound, then react thecompound (6) in the presence of a base and further with the compoundClCOOR⁵ to produce the compound (3). R¹, R², R⁴ and R⁵ are as describedhereinabove.

The mode of practice of the step of producing the compound (6) from thecompound (2) is as described above. The mode of practice of the step ofderiving the compound (3) from the compound (6) is also as describedabove, wherein the base is an alkali metal compound or an alkaline earthmetal compound. As the alkali metal compound, there may be mentionedorganolithium compounds, organopotassium compounds and, further, alkalimetal hydrides. Among those, alkali metal hydrides, such as sodiumhydride, potassium hydride and lithium hydride, are preferred, andsodium hydride is more preferred. As the alkaline earth metal compound,there may be mentioned such organomagnesium compounds as mentionedhereinabove.

After the reaction, the compound (3) or compound (6) formed can berecovered by extraction with an organic solvent such as ethyl acetate,ether, hexane or toluene and, if necessary, can be purified and isolatedby such a procedure as chromatography, crystallization or distillation.The compound (3) or compound (6) is generally formed as a diastereomermixture. However, the diastereomeric excess can be appropriatelyincreased by crystallization. Here, the diastereomeric excess is definedas follows:[(amount of diastereomer A− amount of diastereomer B)/(amount ofdiastereomer A+ amount of diastereomer B)]×100.

The solvent to be used in crystallization is not particularly restrictedbut includes, among others, pentane, hexane, heptane, octane, water,methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol,tert-butanol, benzene, xylene, trimethylbenzene, tetrahydrofuran,tetrahydropyran, 1,3-dioxane, 1,4-dioxane, methyl acetate, ethylacetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutylacetate, tert-butyl acetate, dimethyl ether, tert-butyl methyl ether,acetonitrile, propionitrile, butyronitrile, acetone, DMF, dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), and mixed solventscomprising two or more of these. The crystallization condition can beproperly determined.

The reaction product can be used in the next step without extraction, ifnecessary after dehydration or dehydration and concentration.

The step of producing the compound (4) from the compound (3) is nowdescribed. In this step, the compound (4) is produced by reacting thecompound (3) with a compound represented by the formula MOR⁶. R¹, R², R⁴and R⁵ are as described hereinabove.

As R⁶ in the formula MOR⁶, there may be mentioned a substituted orunsubstituted alkyl group containing 1 to 20 (preferably 1 to 10, morepreferably 1 to 6) carbon atoms, such as, for example, methyl group,ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutylgroup, sec-butyl group, tert-butyl group, n-pentyl group, sec-pentylgroup and isopentyl group. Methyl group and ethyl group are preferred,and methyl group is more preferred.

M represents an alkali metal atom such as a lithium atom, sodium atomand potassium atom. A sodium atom is preferred.

As for the usage of the compound represented by the formula MOR⁶, thatcompound is generally used in an amount of not less than 1 mole,preferably 1.1 to 3.0 moles, per mole of the compound (3). When used incombination in an amount of not less than 1.0 mole per mole of thecompound (3), however, the amount of MOR⁶ may be 1.0 mole or less permole of the compound (3). When R⁶OH is used, the amount thereof is notless than 1.0 mole per mole of the compound (3), without any furtherparticular restriction. Furthermore, in that case, the amount of MOR⁶ ispreferably 0.01 to 10.0 moles, more preferably 0.1 to 3.0 moles, stillmore preferably 0.5 to 2.5 moles, per mole of the compound (3).

The solvent to be used is not particularly restricted but may be any ofthose which will not adversely affect the reaction. Thus, there may bementioned, in addition to the above-mentioned R⁶OH, hexane, toluene,xylene, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, DMF,DMSO, NMP, and mixtures of these. Among them, hexane and tetrahydrofuranare particularly preferred.

The reaction is generally carried out at −20° C. to 50° C., preferably−10° C. to 30° C. The reaction time is generally 0.5 hour to 24 hours,preferably 1 hour to 18 hours.

After the reaction, the compound (4) formed can be recovered byextraction with an organic solvent such as ethyl acetate, toluene,hexane or ether and, if necessary, can be purified by such a procedureas chromatography, crystallization or distillation. The reaction mixturemay be used in the next step without extraction, if necessary afterdehydration or dehydration and concentration.

The step of deriving the compound (8) from the compound (7) is nowdescribed. R⁴ is as described hereinabove. In the relevant formula, R⁷and R⁸ each represents an alkyl group containing 1 to 18 carbon atoms,an aryl group containing 6 to 20 carbon atoms or an aralkyl groupcontaining 7 to 20 carbon atoms and they maybe bound together to form aring. Furthermore, an asymmetric carbon atom may be contained therein.

The alkyl group is a substituted or unsubstituted one containing 1 to 18(preferably 1 to 10, more preferably 1 to 6) carbon atoms, such as, forexample, methyl group, ethyl group, n-propyl group, isopropyl group,n-butyl group, isobutyl group, sec-butyl group, tert-butyl group,n-pentyl group, isopentyl group or n-hexyl group.

The aryl group is a substituted or unsubstituted one containing 6 to 20(preferably 6 to 10) carbon atoms, such as, for example, phenyl group,1-naphthyl group, 2-naphthyl group, 4-methylphenyl group, 3-methylphenylgroup, 2-methylphenyl group, 4-ethylphenyl group, 3-ethylphenyl group,4-methoxyphenyl group, 3-methoxyphenyl group, 2-methoxyphenyl group,4-nitrophenyl group, 4-phenylphenyl group, 4-chlorophenyl group or4-bromophenyl group.

The aralkyl group is a substituted or unsubstituted one containing 7 to20 (preferably 7 to 10) carbon atoms, such as, for example, benzylgroup, 4-methylbenzyl group, 3-methylbenzyl group, 2-methylbenzyl group,4-methoxybenzyl group, 3-methoxybenzyl group, 2-methoxybenzyl group,1-phenylethyl group, 2-phenylethyl group, 3-phenylpropyl group or2-phenylpropyl group.

In cases where R⁷ and R⁸ are bound together, the compound of the formula(7) is represented by the following formula (9);

; or the following formula (10);

wherein R⁴, X, Y and * are as defined hereinabove and R¹⁰, R¹¹, R¹²,R¹³, R¹⁴ and R¹⁵ each independently represents a substituted orunsubstituted alkyl group containing 1 to 18 carbon atoms, a substitutedor unsubstituted aryl group containing 6 to 20 carbon atoms or asubstituted or unsubstituted aralkyl group containing 7 to 20 carbonatoms.

Preferred as R⁷ is 1-phenylethyl group having the (R) or (S) absoluteconfiguration. Preferred as R⁸ are phenyl group and isopropyl group.

In the formulas (7), (9) and (10), X represents C, S or S(O), and Yrepresents CH, O or NH. Carbon is preferred as X, and oxygen ispreferred as Y.

As R⁹ in the formula MOR⁹, there may be mentioned a hydrogen atom or asubstituted or unsubstituted alkyl group containing 1 to 20 (preferably1 to 10, more preferably 1 to 6) carbon atoms, such as, for example,methyl group, ethyl group, n-propyl group, isopropyl group, n-butylgroup, isobutyl group, sec-butyl group, tert-butyl group, n-pentylgroup, sec-pentyl group and isopentyl group. Among them, methyl groupand ethyl group are preferred, and methyl group is more preferred.

M represents an alkali metal atom, such as a lithium atom, sodium atomor potassium atom. A sodium atom is preferred.

As for the usage, the compound represented by the formula MOR⁹ isgenerally used in an amount of not less than 1 mole, preferably 1.1 to3.0 moles, per mole of the compound (7). When R⁹OH (wherein R⁹ is otherthan H) is used in combination in an amount of not less than 1.0 moleper mole of the compound (7), however, the amount of MOR⁹ may be 1.0mole or less per mole of the compound (7). When R⁹OH is used, the amountthereof is not less than 1.0 mole, without any further particularrestriction. Furthermore, in that case, the amount of MOR⁹ is preferably0.01 to 10.0 moles, more preferably 0.1 to 3.0moles, still morepreferably 0.5 to 2.5 moles, per mole of the compound (7).

When R⁹ in MOR⁹ is a hydrogen atom, it is generally possible to carryout the reaction in the presence of hydrogen peroxide according to needand, in this case, the compound (8) formed is a 2-allylcarboxylic acidrepresented by the formula (5) given hereinabove. When R⁹ is other thana hydrogen atom, the compound (8) formed is a 2-allylcarboxylic acidester represented by the formula (4) given hereinabove. When the productis a 2-allylcarboxylic acid ester (4), this may be converted to thecorresponding 2-allylcarboxylic acid (5) by hydrolysis according toneed. When hydrogen peroxide is used, this is used generally in anamount of not less than 1.0 mole, preferably 1.0 to 50 moles, morepreferably 1.1 to 30 moles, per mole of MOR⁹.

The solvent to be used is not particularly restricted but may be any ofthose which will not adversely affect the invention. Thus, there may bementioned, in addition to above mentioned R⁹OH, hexane, toluene, xylene,tetrahydrofuran, diethyl ether, tert-butyl methyl ether, DMF, DMSO, NMP,and mixed solvents composed of two or more of these. Preferred arehexane and tetrahydrofuran, in particular.

The reaction is generally carried out at −20° C. to 50° C., preferably−10° C. to 30° C. The reaction time is generally 0.5 hour to 24 hours,preferably 1 hour to 18 hours.

After the reaction, the compound (8) formed can be recovered byextraction with an organic solvent such as ethyl acetate, toluene,hexane or ether and, if necessary, can be purified by such a procedureas chromatography, crystallization or distillation. The reaction mixturemay be used in the next step without extraction, if necessary afterdehydration or dehydration and concentration.

Finally, the step of producing the compound (5) from the compound (4) isdescribed. R⁴ and R⁶ are as described hereinabove. In this step, any ofthose methods generally used in hydrolyzing esters can be employedwithout any particular restriction. More preferably, however, thecompound (4) is stereoselectively hydrolyzed using an enzyme sourcecapable of asymmetrically hydrolyzing the same to give a productimproved in optical purity. The compound (4) to be used may be either aracemic mixture or an optically active form.

The enzyme source is not particularly restricted but may be any onecapable of stereoselectively hydrolyzing the ester moiety of thecompound (4). The enzyme may be a microorganism-derived, animalcell-derived or plant cell-derived one. Specifically, there may bementioned enzyme sources derived from microorganisms belonging to thegenus Candida, Humicola, Mucor, Pseudomonas, Rhizopus, Brevundimonas,Cellulomonas, Jensenia, Rhodococcus, Saccharomycopsis or Trichosporon.

More specifically, mention may be made of enzyme sources derived fromCandida antarctica, Candida lipolitica, Candida cylindracea, Candidarugosa, Humicola sp., Humicola lanuginosa, Mucor meihei, Mucorjavanicus, Pseudomonas sp., Rhizopus delemar, Rhizopus javanicus,Brevundimonas diminuta, Cellulomonas fimi, Jensenia canicruria,Rhodococcus erythropolis, Candida pini, Saccharomycopsis selenospora,Trichosporon cutaneum or Trichosporon debeurmannianum.

The “enzyme source” so referred to herein includes not only purifiedenzymes but also roughly purified enzymes and microbial cells, and thelike. Furthermore, the enzyme or microbial cells may be immobilized onan inorganic carrier, organic polymer carrier, and/or the like.

The hydrolysis reaction using the enzyme source mentioned above may becarried out in water or in a mixed solvent composed of water and anorganic solvent. The organic solvent to be used in admixture with wateris, for example, methanol, ethanol, propanol, acetone, dioxane,tetrahydrofuran, toluene or ethyl acetate. The substrate compound (4) orcompound (8) is used in an amount within the range of 0.1 to 50% byweight on the reaction mixture basis, and the enzyme source is used inan amount of 0.01 to 500% byweight based on the substrate, although theamount thereof may depend on the mode of utilization thereof. The enzymesource may be added either all at once at the start of the reaction orin divided portions. Similarly, the substrate compound (4) or compound(8) may be added either all at once at the start of the reaction or individed portions.

The temperature at which the enzyme source is to act on the substrate ispreferably 10 to 60° C., more preferably 25 to 40° C., and may depend onthe properties of the enzyme.

The pH of the reaction mixture is preferably within the range of 3 to10, more preferably within the range of 5 to 8. For the pH adjustment ofthe solution, an aqueous solution of an alkali such as sodium hydroxideor sodium carbonate may be used or, alternatively, a buffer solutionsuch as a phosphate buffer may be used. The pH value may be decreasedwith the progress of the reaction in some instances. As long as the pHvalue is within the above-mentioned preferred range, no pH adjustmentwill be required. Optionally, the pH value may be maintained at aconstant level by adequate addition of an aqueous solution of an alkali.

After completion of the reaction, the unreacted optically activecompound (4) or compound (8) maybe isolated by adjusting the reactionmixture to an alkaline pH by addition thereto of an aqueous solution ofan alkali such as sodium hydroxide and extracting the organic phase withan organic solvent such as ethyl acetate, hexane or toluene. Afterextraction with the organic phase, the aqueous phase is adjusted to anacidic pH by addition thereto of an acid such as sulfuric acid andextracted with such an organic solvent as ethyl acetate, hexane ortoluene, where-upon the optically active compound (5), which is thehydrolysis product, can be isolated. Furthermore, each compound can bepurified by distillation, silica gel column chromatography, and thelike.

BEST MODES FOR CARRYING OUT THE INVENTION

The following examples illustrate the present invention in furtherdetail. These are, however, by no means limitative of the scope of theinvention.

Preparation Example 1 (R)-N-Octanoyl-1-phenylethylamine

A solution of 50.0 g (412.6 mmol) of (R)-1-phenylethylamine and 41.75 g(412.6 mmol) of triethylamine in 750 ml of toluene was cooled to 0° C.,and 73.85 g (453.9 mmol) of octanoyl chloride was added dropwisethereto. After completion of the addition, the reaction was allowed toproceed at room temperature for 3 hours. The reaction mixture was againcooled to 0° C. and then the reaction was terminated by addition of 200ml of 10% hydrochloric acid. The toluene phase was separated, washedwith 300 ml of a 10% aqueous solution of sodium hydroxide, and driedover anhydrous sodium sulfate. The solvent was then distilled off, andthe residue was quantitated by HPLC. Thus was obtained 19.81 g (97%) ofthe title compound.

¹H-NMR (400 MHz, CDCl₃) δ 0.87 (t, 3H, J=7.3 Hz), 1.26-1.29 (m, 8H),1.48 (d, 3H, J=7.1 Hz), 1.61-1.64 (m, 2H), 2.17 (t, 2H, J=7.3 Hz), 5.15(q, 1H, J=7.1 Hz), 5.64 (brs, 1H), 7.28-7.36 (m, 5H).

Preparation Examples 2 to 5

The compounds given in Table 1 were obtained in the same manner as inPreparation Example 1. TABLE 1 Preparation Yield Example Compound (%)¹H-NMR (400 Mz, CDCl₃) 2

95 0.87 (t, 3 H, J = 7.3 Hz), 1.26-1.30 (m, 8 H), 1.46 (d, 3 H, J = 6.8Hz), 1.61 (t, 2 H, J = 7.1 Hz), 2.15 (q, 2 H, J = 7.3 Hz), 3.79 (s, 3H), 5.09 (q, 1 H, J = 6.8 Hz), 5.70 (brs, 1 H), 6.85-6.88 (m, 2 H)7.22-4.26 (m, 2 H). 3

96 0.86 (t, 3 H, J = 7.3 Hz), 1.28-1.30 (m, 8 H), 1.46 (d, 3 H, J = 7.1Hz), 1.59-1.70 (m, 2 H), 2.17-2.32 (m, 2 H), 3.79 (s, 3 H), 5.08 (m, 1H), 5.82-5.77 (m, 1 H), 6.73-6.89 (m, 3 H), 7.21-7.29 (m, 1 H). 4

98 0.86 (t, 3 H, J = 7.3 Hz), 1.23-1.26 (m, 8 H), 1.60-1.63 (m, 2 H),1.67 (d, 2 H, J = 6.6 Hz), 2.12-2.17 (m, 2 H), 5.62 (brs, 1 H), 5.95 (q,1 H, J = 6.6 Hz), 7.44-7.56 (m. 4H), 7.79-7.88 (m, 2 H), 8.09 (d, 1 H, J= 8.1 Hz). 5

96 0.87 (t, 3 H, J = 7.3 Hz), 1.23-1.29 (m, 8 H), 1.51-1.57 (m, 2 H),2.11 (t, 2 H, J = 7.3 Hz), 2.29 (s, 3 H), 3.00-3.12 (m, 2 H), 5.27 (q, 1H, J = 7.3 Hz), 5.65 (brs, 1 H), 6.94 (d, 2 H, J = 8.1 Hz), 7.03 (d, 2H, J = 8.1 Hz), 7.26-7.32 (m, 5 H).

Preparation Example 6 (R)-N-Octanoyl-1-phenylethylamine

Octanoic anhydride (5.58 g, 20.6 mmol) was added dropwise to a solutionof 2.75 g (22.7 mmol) of (R)-1-phenylethylamine and 2.09 g (20.6 mmol)of triethylamine in 35 ml of toluene at room temperature. The reactionwas allowed to proceed for 18 hours and then the reaction was terminatedby addition of 20 ml of 10% hydrochloric acid. The toluene phase wasseparated, washed with two 30-ml portions of 10% sodium hydroxide anddried over anhydrous sodium sulfate. After removal of the solvent bydistillation, the residue was quantitated by HPLC. Thus was obtained4.55 g (89%) of the title compound.

Preparation Example 7 (R)-N-Allyl-N-octanoyl-1-phenylethylamine

Sodium hydride (60%) (0.65 g, 16.3 mmol) was washed with three 20-mlportions of hexane and then suspended in 5 ml of THF. Hereto were addeda solution of 2.00 g (8.1 mmol) of (R)-N-octanoyl-1-phenylethylamine in15 ml of THF, and 1.96 g (16.3 mmol) of allyl bromide, and the reactionwas allowed to proceed at room temperature for 1 hour and, then, at 70°C. for 2 hours. The reaction mixture was cooled to room temperature andadded dropwise to 20 ml of ice-cooled 1 M hydrochloric acid to therebyterminate the reaction. The resulting mixture was extracted with 30 mlof hexane. The organic phase was washed with a saturated aqueoussolution of sodium chloride and dried over anhydrous sodium sulfate, andthe solvent was then distilled off. The desired product was purified ona silica gel column. Thus was obtained 7.59 g (94%) of the titlecompound.

¹H-NMR (400 MHz, CDCl₃) δ 0.87 (t, 3H, J=7.3 Hz), 1.28-1.30 (m, 8H),1.48 (d, 3H, J=7.1 Hz), 1.61-1.68 (m, 2H), 2.81 (t, 2H, J=7.3 Hz),3.58-3.74 (m, 2H), 4.96-5.08 (m, 2H), 5.55-5.62 (m, 1H), 6.12 (q, 1H,J=7.1 Hz), 7.23-7.36 (m, 5H).

Preparation Examples 8 TO 11

The compounds given in Table 2 were obtained in the same manner as inPreparation Example 7. TABLE 2 Preparation Yield Example Compound (%)¹H-NMR (400 Mz, CDCl₃) 8

99 0.86-0.89 (m, 3 H), 1.28-1.30 (m, 8 H), 1.45 (d, 2 H, J = 7.3 Hz),1.57-1.69 (m, 3 H), 2.17-2.47 (m, 2H), 3.37-4.08 (m, 5 H), 4.96-5.13 (m,2 H), 5.52-6.10 (m, 2 H), 6.84-6.89 (m, 2 H), 7.21-7.27 (m, 2 H). 9

96 0.84-0.87 (m, 3 H), 1.25-1.28 (m, 8 H), 1.47 (d, 2 H, J = 6.8 Hz),1.61-1.64 (m, 3 H), 2.31-2.35 (m, 2 H), 3.61-3.67 (m, 1 H), 3.70-3.80(m, 4 H), 5.07-5.14 (m, 2 H), 5.50-5.69 (m, 1 H), 6.06-6.10 (m, 1 H). 10

93 0.85-0.88 (m, 3 H), 1.26-1.29 (m, 8 H), 1.43-1.70 (m, 5 H), 2.29 (t,2 H, J = 7.5 Hz), 2.58-3.61 (m, 2H), 4.76-4.80 (m, 2 H), 5.10-5.18 (m, 1H), 6.69-6.74 (m, 1 H), 7.44-7.55 (m, 4 H), 7.80-7.86 (m, 2 H),8.01-8.03 (m, 1 H). 11

94 0.87 (t, 3 H, J = 7.3 Hz), 1.23-1.26 (m, 8 H), 1.30 (t, 2 H, J = 6.8Hz), 1.56-1.58 (m, 2H), 2.17 (t, 2 H, J = 7.1 Hz), 2.27 (s, 3 H),3.22-3.30 (m, 2 H), 3.61-3.79 (m, 2 H), 4.84-4.95 (m, 2 H), 6.22 (t, 1H, J = 8.1 Hz), 7.04-7.23 (m, 4 H), 7.28-7.40 (m, 5 H).

Preparation Example 12 (R)-N-Allyl-N-octanoyl-1-phenylethylamine

A solution of 10.0 g (40.0 mmol) of (R)-N-octanoyl-1-phenylethylamine in20 ml of toluene, and 9.90 g (80.0 mmol) of allyl bromide were added toa suspension of 3.20 g (80.0 mmol) of sodium hydride (60%) in 74 ml oftoluene, and the reaction was allowed to proceed at 100° C. for 6 hours.The reaction mixture was cooled to room temperature and added dropwiseto 80 ml of ice-cooled 1 N hydrochloric acid to thereby terminate thereaction. The resulting mixture was extracted with three 30-ml portionsof hexane. The organic phase was washed with 50 ml of water and thendried over anhydrous sodium sulfate, and the solvent was distilled off.The residue was quantitated by HPLC. Thus was obtained 9.87 g (86%) ofthe title compound.

Example 1 (R)-N-(2-Allyloctanoyl)-1-phenylethylamine

To a solution of 24.0 g (83.0 mmol) of(R)-N-allyl-N-octanoyl-1-phenylethylamine in 240 ml of toluene was addeddropwise 61.5 ml (98.0 mmol) of tert-butylmagnesium chloride (1.6 M) atroom temperature and, after completion of the addition, the reaction wasallowed to proceed at 70° C. for 6 hours. After completion of thereaction, the reaction mixture was added dropwise to 240 ml of 1 Naqueous hydrochloric acid on an ice bath. The resulting mixture wasextracted with 300 ml of hexane, and the organic layer was washed with100 ml of a saturated aqueous solution of sodium chloride and thenconcentrated under reduced pressure to give 25.0 g of a crude product.The crude product was purified by column chromatography on silica gel(hexane:ethyl acetate=10:1) to give 13.1 g (76%, (1R,2S):(1R,2R)=80:20)of N-[(R)-2-allyloctanoyl]-1-phenylethylamine.

¹H-NMR (400 MHz, CDCl₃) δ 0.83-0.87 (m, 3H), 1.18-1.23 (m, 8H),1.42-1.50 (m, 4H), 1.52-1.59 (m, 1H), 2.01-2.06 (m, 1H), 2.14-2.21 (m,1H), 2.33-2.41 (m, 1H), 4.94-5.20 (m, 3H), 5.60-5.81 (m, 1H), 7.23-7.33(m, 5H)

EXAMPLES 2 TO 7

The compounds given in Table 3 were obtained in the same manner as inExample 1. TABLE 3 Yield (%) (Diastereomar Example Compound Solventratio) ¹H-NMR (400 MHz, CDCl₃) 2

THF 46 (1S, 2R):(1S, 2S) =72:28 As described in Example 1 3

Hexane 72 (1S, 2R):(1S, 2S) =82:18 As described in Example 1 4

Toluene 77 (1R, 2S):(1R, 2R) =81:19 0.86-0.86 (m, 3 H), 1.21-1.26 (m, 8H), 1.45-1.46 (m, 3 H), 1.59-1.67 (m, 2 H), 2.02-2.34 (m, 3 H), 3.79 (s,3 H), 4.94-5.13 (m, 2 H), 6.86 (d, 2 H, J = 7.3 Hz), 7.23 (d, 2 H, J =7.3 Hz) 5

Toluene 80 (1R, 2S):(1R, 2R) =77:23 0.82-0.86 (m, 3 H), 1.20-1.45 (m, 8H), 1.43-1.45 (m, 4 H), 1.55-1.62 (m, 1 H), 2.10-2.18 (m, 2 H),2.34-2.36 (m, 1 H), 3.77 (s, 3 H), 4.93-5.12 (m, 3 H), 5.61-5.76 (m, 1H), 5.98-6.10 (m, 1 H), 6.77 (d, 1 H, J = 7.1 Hz), 6.85-6.90 (m, 2 H),7.21-7.24 (m, 1 H). 6

Toluene 60 (1S, 2R*):(1S, 2S*) =72:28 0.80-0.88 (m, 3 H), 1.15-1.36 (m,8 H), 1.60-1.75 (m, 5 H), 1.98-2.04 (m, 1 H), 2.16-2.18 (m, 1 H),2.25-2.38 (m, 1 H), 5.00-5.08 (m, 2 H), 5.72-5.76 (m, 1 H), 5.93-5.95(m, 1 H). 7.45-7.51 (m, 4 H), 7.79-7.86 (m, 2 H), 8.09-8.11 (m, 1 H). 7

Toluene 81 (1S, 2R*):(1S, 2S*) =85:15 0.82-0.89 (m, 3 H), 2.14-1.20 (m,8 H), 1.59 (s, 3 H), 1.99-2.26 (m, 2 H), 2.29 (S, 3 H), 2.96-3.00 (m, 1H), 3.01-3.11 (m, 1 H), 4.87-4.98 (m, 2 H), 5.26-5.31 (m, 1 H),5.47-4.57 (m, 1 H), 5.66-5.67 (m, 1 H), 6.96-7.05 (m, 4 H), 7.24-7.52(m, 5 H).

Example 8 N-(2-Allyloctanoyl)-(R)-1-(3-methoxyphenyl)ethylaminediastereomer purification

n-Pentane (25 ml) was added to 1.0 g of anN-(2-allyloctanoyl)-(R)-1-(3-methoxyphenyl)ethylamine diastereomermixture ((1R,2S):(1R,2R)=77:23), and the mixture was warmed to 40° C.and then allowed to cool slowly to room temperature. The crystallineprecipitate was collected by filtration. Thus was obtained 0.47 g (58%recovery upon recrystallization, diastereomer ratio(1R,2S):(1R,2R)=94:6) of the title compound.

Example 9 N-(2-Allyloctanoyl)-(S)-1-phenyl-2-(4-methylphenyl)ethylaminediastereomer purification

Acetone (6 ml) was added to 1.0 g of anN-(2-allyloctanoyl)-(S)-1-phenyl-2-(4-methylphenyl)ethylaminediastereomer mixture ((1S,2R*):(1S,2S*)=85.3:14.7) and, afterdissolution at 50° C., 20 ml of hexane was added, and the resultingmixture was allowed to cool slowly to room temperature. The crystallineprecipitate was collected by filtration to give 0.40 g of crystals ((1S,2R*):(1S,2S*)=95.7:4.3). Acetone (4 ml) was added to the crystalsobtained and, after dissolution at 50° C., 10 ml of hexane was added,and the resulting mixture was allowed to cool slowly to roomtemperature. The crystalline precipitate was collected by filtration togive 0.17 g of white crystals (25% recovery upon recrystallization,(1S,2R*):(1S,2S*)=99.3:0.7).

Example 10N-Isopropyloxycarbonyl-N-(2-allyloctanoyl)-(R)-1-phenylethylamine

To a solution of 40.0 g (0.14 mol) of(R)-N-allyl-N-octanoyl-1-phenylethylamine in 400 ml of toluene was addeddropwise 105 ml (0.17 mol) of tert-butylmagnesium chloride (1.6 M) atroom temperature, and the reaction was allowed to proceed at 70° C. for6 hours. The reaction mixture was cooled to room temperature and, then,51.0 g (0.42 mol) of isopropyl chlorocarbonate was added, and thereaction was allowed to proceed at room temperature for 15 hours. Aftercompletion of the reaction, the reaction mixture was added dropwise to170 ml of a 1 N aqueous solution of hydrochloric acid in an ice bath.The reaction mixture was extracted with 400 ml of hexane, and theorganic layer was washed with 100 ml of a saturated aqueous solution ofsodium chloride and then concentrated under reduced pressure to give52.1 g of a crude product. The crude product was purified by columnchromatography on silica gel (hexane:ethyl acetate=10:1) to give 41.0 gof the title compound as a colorless oil (yield 78%, diastereomer ratio(1R,2S):(1R,2R)=80:20).

¹H-NMR (400 MHz, CDCl₃) δ 0.72 (d, 3H, J=7.3 Hz), 0.82-0.83 (m, 3H),1.16 (d, 3H, J=7.3 Hz), 1.18-1.20 (m, 8H), 1.48-1.52 (m, 3H), 1.57-1.69(m, 3H), 2.22-2.49 (m, 1H), 3.58 (m, 1H), 4.77-4.81 (m, 1H), 4.90-5.19(m, 2H), 5.68-77 (m, 1H), 5.98-6.02 (m, 1H), 7.20-7.41 (m, 5H).

Examples 11 TO 14

The following compounds were obtained in the same manner as in Example10.

TABLE 4 CICOOR (amount used; Yield Example R equivalents) (%)¹H-NMR(400MHz, CDCl₃) 11 COOMe 3.0 86 0.88(t, 3H, J=7.3Hz), 1.21-1.29(m,8H), 1.52-1.55(m, 3H) 1.66(d, 3H, J=6.8Hz), 2.22-2.52(m, 2H),3.34-3.48(m, 1H) 3.52(s, 3H), 4.97-5.30(m, 2H), 5.66-5.82(m, 1H),5.97-5.98(m, 1H), 7.21-7.30(m, 5H). 12 COO-sec-Bu 1.0 54 0.54(m, 3H),0.85-0.94(m, 6H), 1.17-1.49(m, 10H), 1.52-1.67(m, 2H), 1.75-1.80(m, 3H),2.24-2.56(m, 2H), 3.50-3.65(m, 1H), 4.61-4.68(m, 1H), 4.98-5.17(m, 2H),5.70-5.85(m, 1H), 6.01-7.20(m, 5H). 13 COOPh 2.0 94 0.85-0.87(m, 3H),1.26-1.39(m, 8H), 1.55-1.56(m, 2H), 1.78(d, 3H, J=6.8Hz), 2.27-2.31(m,1H), 2.43-2.50(m, 1H) 3.61-3.64(m, 1H), 5.03-5.10(m, 2H), 5.72-5.86(m,1H), 6.17-6.20(m, 1H), 7.16-7.44(m, 10H). 14 COO-4-NO₂Ph 2 690.85-0.87(m, 3H), 1.22-1.36(m, 8H), 1.55-1.57(m, 2H), 1.77(d, 3H,J=6.8Hz), 2.27-2.31(m, 1H), 2.39-2.41(m, 1H), 3.60-3.64(m, 1H),5.03-5.10(m, 2H), 5.72-5.88(m, 1H), 6.10-6.12(m, 1H), 7.44(d, 2H,J=9.0Hz), 8.33(d, 2H, J=9.0Hz).

EXAMPLE 15N-Ethyloxycarbonyl-N-(2-allyloctanoyl)-(R)-1-(3-methoxyphenyl)ethylamine

A solution of 0.40 g (1.3 mmol) ofN-(2-allyloctanoyl)-(R)-1-(3-methoxyphenyl)ethylamine (diastereomerratio (1R,2S):(1R,2R)=77:23) in 2 ml of DMF was added to a solution of151 mg (3.8 mmol) of sodium hydride in 2 ml of DMF at room temperature,and the reaction was allowed to proceed at 50° C. for 1 hour. To thereaction mixture was added 0.48 ml (5.0 mmol) of ethyl chlorocarbonate,and the mixture was stirred at 50° C. for 12 hours. The reaction mixturewas added dropwise to a mixed solution composed of 5 ml of a 1 N aqueoussolution of hydrochloric acid and 5 ml of hexane with ice cooling, andthe resulting mixture was extracted with two 20-ml portions of hexane.The organic layer was washed with 5 ml of a saturated aqueous solutionof sodium chloride and concentrated under reduced pressure to give 0.49g of a crude product. The crude product was purified on a silica gelcolumn (ethyl acetate:hexane=20:1) to give 0.224 g of the title compoundas a colorless oil (yield 46%, (1R,2S):(1R,2R)=77:23).

¹H-NMR (400 MHz, CDCl₃) δ 0.86-0.88 (m, 3H), 0.98-1.03 (m, 3H),1.22-1.27 (m, 8H), 1.62-1.68 (m, 2H), 1.81-185 (m, 3H), 2.20-2.55 (m,2H), 3.52 (m, 1H), 3.78 (s, 3H), 3.82-4.02 (m, 2H), 4.98-5.11 (m, 2H),5.70-5.76 (m, 1H), 5.83-5.98 (m, 1H), 6.75-6.86 (m, 3H), 7.19-7.26 (m,1H).

Example 16 Methyl 2-allyloctanoate

A solution of 0.345 g (1.0 mmol) ofN-methyloxycarbonyl-N-(2-allyloctanoyl)-1-(R)-phenylethylamine in 5 mlof methanol was cooled to 0° C., 0.386 g (2.0 mmol) of NaOMe (28%solution in methanol) was added, and the mixture was stirred for 22hours. The reaction was terminated by addition of 2 ml of 1 Nhydrochloric acid, and the product was extracted with ethyl acetate. Theextract was dried over anhydrous sodium sulfate, the solvent wasdistilled off, and the residue was isolated/purified on a silica gelcolumn to give 0.10 g (51%) of the title compound.N-(2-Allyloctanoyl)-(R)-1-phenylethylamine was formed as a byproduct in45% yield.

¹H-NMR (400 MHz, CDCl₃) δ 0.87 (t, 3H, J=6.8 Hz), 1.24-1.28 (m, 8H),1.54-1.56 (m, 3H), 2.20-2.45 (m, 2H), 3.66 (s, 3H), 4.99-5.04 (m, 2H),5.68-5.78 (m, 1H).

Example 17 Methyl 2-allyloctanoate

A solution of 0.345 g (1.0 mmol) ofN-methyloxycarbonyl-N-(2-allyloctanoyl)-1-(R)-phenylethylamine in 5 mlof THF was cooled to 0° C., 0.386 g (2.0 mmol) of NaOMe (28% solution inmethanol) was added, and the mixture was stirred for 22 hours. Thereaction was terminated by addition of 2 ml of 1 N hydrochloric acid,and the product was extracted with ethyl acetate. The extract was driedover anhydrous sodium sulfate, the solvent was distilled off, and theresidue was quantitated by GC. Thus was obtained 0.109 g (55%) of thetitle compound.

N-(2-Allyloctanoyl)-(R)-1-phenylethylamine was formed as a byproduct in36% yield.

Example 18 Methyl 2-allyloctanoate

A solution of 25.12 g (67.5 mmol) ofN-isopropyloxycarbonyl-N-(2-allyloctanoyl)-1-(R)-phenylethylamine((1R,2S):(1R,2R)=77:23) in 338 ml of THF was cooled to −10° C., 26.1 g(135 mmol) of NaOMe (28% solution in methanol) was added dropwise and,after completion of the addition, the mixture was further stirred for 45minutes. The reaction was terminated by addition of 120 ml of 1 Nhydrochloric acid, and the product was extracted with hexane (100 ml×2).The extract was dried over anhydrous sodium sulfate, and the solvent wasdistilled off to give 25.90 g of a crude product. This was purified on asilica gel column to give 12.32 g (92%, 54% ee) of the title compound.

Example 19 Methyl 2-allyloctanoate

A solution of 40 g (110 mmol) ofN-isopropyloxycarbonyl-N-(2-allyloctanoyl)-1-(R)-phenylethylamine((1R,2S):(1R,2R)=80:20) in 400 ml of hexane was cooled to 0° C., 41.5 g(220 mmol) of NaOMe (28% solution in methanol) was added dropwise and,after completion of the addition, the mixture was further stirred for 5hours. The reaction was terminated by addition of 230 ml of 1 Nhydrochloric acid, and the product was extracted with hexane (400 ml).The organic layer was washed with 100 ml of a saturated aqueous solutionof sodium hydrogen carbonate and then with 100 ml of water and driedover anhydrous sodium sulfate, and the solvent was distilled off. Theresidue was quantitated by GC. Thus was obtained 103.42 g (94%, 60% ee)of the title compound.

Example 20 Methyl 2-allyloctanoate

A solution of 0.374 g (1.0 mmol) ofN-isopropyloxycarbonyl-N-(2-allyloctanoyl)-1-(R)-phenylethylamine((1R,2S):(1R,2R)=77.6:22.4) in 5 ml of THF was cooled to 0° C., 0.386 g(2.0 mmol) of NaOMe (28% solution in methanol) was added, and themixture was stirred for 1 hour. The reaction was terminated by additionof 2 ml of 1 N hydrochloric acid, and the product was extracted withethyl acetate (30 ml×2). The extract was dried over anhydrous sodiumsulfate, and the solvent was distilled off. The residue was quantitatedby GC. Thus was obtained 0.165 g (83%, 55.3% ee) of the title compound.

Example 21 Methyl 2-allyloctanoate

A solution of 0.374 g (1.0 mmol) ofN-isopropyloxycarbonyl-N-(2-allyloctanoyl)-1-(R)-phenylethylamine((1R,2S):(1R,2R)=77.6:22.4) in 5 ml of THF was cooled to 0° C. Asolution of 11 mg (0.2 mmol) of NaOMe in methanol (0.04 g) was added,and the mixture was stirred for 7 hours. The reaction was terminated byaddition of 1 ml of 1 N hydrochloric acid, and the product was extractedwith ethyl acetate (30 ml×2). The extract was dried over anhydroussodium sulfate, and the solvent was distilled off. The residue wasquantitated by GC. Thus was obtained 0.163 g (82%, 55.0% ee) of thetitle compound.

Example 22 Methyl 2-allyloctanoate

A solution of 0.374 g (1.0 mmol) ofN-isopropyloxycarbonyl-N-(2-allyloctanoyl)-1-(R)-phenylethylamine((1R,2S):(1R,2R)=77.6:22.4) in 5 ml of toluene was cooled to 0° C.,0.386 g (2.0 mmol) of NaOMe (28% solution in methanol) was added, andthe mixture was stirred for 21 hours. The reaction was terminated byaddition of 2 ml of 1 N hydrochloric acid, and the product was extractedwith ethyl acetate (30 ml×2). The extract was dried over anhydroussodium sulfate, and the solvent was distilled off. The residue wasquantitated by GC. Thus was obtained 0.149 g (75%, 54.2% ee) of thetitle compound.

Example 23 Methyl 2-allyloctanoate

A solution of 0.218 g (0.5 mmol) ofN-phenyloxycarbonyl-N-(2-allyloctanoyl)-1-(R)-phenylethylamine in 2 mlof methanol was cooled to 0° C., 0.38 g (1.0 mmol) of LiOMe was added,and the mixture was stirred for 22 hours. The reaction was terminated byaddition of 2 ml of 1 N hydrochloric acid, and the product was extractedwith ethyl acetate (30 ml×2). The extract was dried over anhydroussodium sulfate, and the solvent was distilled off. The residue wasquantitated by GC. Thus was obtained 0.057 g (58%) of the titlecompound.

Example 24 2-Allyloctanoic acid

An aqueous solution of hydrogen peroxide (31% by weight; 0.5 ml, 55.0mmol) and 0.043 g (1.0 mmol) of lithium hydroxide monohydrate were addeddropwise to a solution of 0.20 g (0.50 mmol) ofN-ethyloxycarbonyl-N-(2-allyloctanoyl)-(R)-1-(3-methoxyphenyl)ethylamine((1R,2S):(1R,2R)=77:23) in a mixture of 4 ml of THF and 1 ml of water onan ice bath. The mixture was stirred on an ice bath for 3 hours and thenat room temperature for 20 hours. A 2 N aqueous solution of sodiumsulfite (5 ml) was added dropwise to the reaction mixture on an icebath, and the resulting mixture was stirred at room temperature for 2hours. Water (15 ml) was added to the reaction mixture, and the wholemixture was washed with 5 ml of ethyl acetate. To the aqueous layer wasadded 2 ml of a 1 N aqueous solution of hydrochloric acid (pH=2), andthe resulting mixture was extracted with two 40-ml portions of ethylacetate. The organic layer was concentrated under reduced pressure togive 0.078 g (83%, 62% ee) of the title compound as a colorless oil.

Example 25 2-Allyloctanoic acid

An aqueous solution of hydrogen peroxide (31% by weight; 0.6 ml, 5.6mmol) and 0.047 g (1.1 mmol) of lithium hydroxide monohydrate were addeddropwise to a solution of 0.20 g (0.56 mmol) ofN-ethyloxycarbonyl-N-(2-allyloctanoyl)-(R)-1-phenylethylamine(diastereomer ratio (1R,2S):(1R,2R)=81:19) in a mixture of 4 ml of THFand 1 ml of water on an ice bath. The mixture was stirred on an ice bathfor 1 hour and then at room temperature for 18 hours. A 2 N aqueoussolution of sodium sulfite (10 ml) was added dropwise to the reactionmixture on an ice bath, and the resulting mixture was stirred at roomtemperature for 1 hour. Water (15 ml) was added to the reaction mixture,and the whole mixture was washed with 5 ml of ethyl acetate. To theaqueous layer was added 6 ml of a 1 N aqueous solution of hydrochloricacid (pH=2), and the resulting mixture was extracted with two 40-mlportions of ethyl acetate. The organic layer was concentrated underreduced pressure to give 0.043 g (42%, 62% ee) of the title compound asa colorless oil.

ExampleS 26 TO 43 2-Allyloctanoic acid and methyl 2-allyloctanoate

A 10-mg portion of each of the commercial enzymes specified in Table 5was weighed in a test tube, 1 ml of 500 mM phosphate buffer (pH 7) and10 mg of racemic methyl 2-allyloctanoate were added and, after tightclosure, shaking was carried out at 30° C. for 26 hours. Aftercompletion of the reaction, the reaction mixture was acidified by adding0.25 ml of 3 M hydrochloric acid and then extracted with 1 ml of ethylacetate. The ethyl acetate phase was analyzed by gas chromatography, andthe degree of conversion, the optical purity of the product,2-allyloctanoic acid, and the optical purity of the remaining substrate,methyl 2-allyloctanoate were determined. The results are shown in Table5. TABLE 5 Optical purity Optical purity of Degree of of the productRemaining substrate conversion Absolute Absolute Example EnzymeManufacturer Source (%) (% e.e.) configuration (% e.e.) configuration 26Novozym CALB L Novozymes Japan Ltd. Candida antarctica 22 98 S 28 R 27Lipase SP525 Novozymes Japan Ltd. Candida antarctica 54 68 S 80 R 28Lipase OF Meito Sangyo Co., Ltd. Candida cylindracea 90 6 R 54 S 29Lipase (Type VII) Sigma Co. Candida cylindracea 52 24 S 26 R 30 LipaseL-049 Biocatalysts Limited Candida lipolitica 87 14 R 94 S 31 Lipase AYSAmano Enzyme Inc. Candida rugosa 94 3 R 47 S 32 Lipase L-053Biocatalysts Limited Humicola lanuginosa 13 53 R 8 S 33 Lipase SP523Novozymes Japan Ltd. Humicola sp. 12 58 R 8 S 34 Lipase L-166PBiocatalysts Limited Mucor javanicus 90 10 R 90 S 35 Lipozyme 10000LNovozymes Japan Ltd. Mucor meihei 59 34 R 49 S 36 Lipase SP388 NovozymesJapan Ltd. Mucor miehei 60 37 R 56 S 37 Lipase WO 2-12 BoehringerMannheim GmbH Pseuedomonas sp. 7 76 S 6 R 38 Lipase D Amano Enzyme Inc.Rhizopus delemar 63 6 R 10 S 39 Lipase L-058 Biocatalysts LimitedRhizopus delemar 32 12 R 6 S 40 Lipase Saiken 50 Nagase ChemtexCorporation Rhizopus javanicus 68 14 R 30 S 41 Lipase SeikagakuCorporation Rhizopus delemar 96 1 R 24 S 42 Olipase 4S Osaka SaikinKenkyusho Rhizopus javanicus 33 10 R 5 S 43 Lipase D Amano Enzyme Inc.Rhizopus delemar 89 3 R 24 S

ExampleS 44 TO 61 2-Allyloctanoic acid and ethyl 2-allyloctanoate

Racemic ethyl 2-allyloctanoate was subjected to the same procedure as inExamples 26 to 43, and the degree of conversion, the optical purity ofthe product, 2-allyloctanoic acid, and the optical purity of theremaining substrate, ethyl 2-allyloctanoate were determined. The resultsare shown in Table 6. TABLE 6 Optical Degree purity of Optical purity ofof the product Remaining substrate conversion Absolute Absolute ExampleEnzyme Manufacturer Source (%) (% e.e.) configuration (% e.e.)configuration 44 Novozym CALB L Novozymes Japan Ltd. Candida antarctica33 96 S 47 R 45 Lipase SP525 Novozymes Japan Ltd. Candida antarctica 5865 S 90 R 46 Lipase OF Meito Sangyo Co., Ltd. Candida cylindracea 95 4 R76 S 47 Lipase (Type VII) Sigma Co. Candida cylindracea 57 36 S 48 R 48Lipase L-049 Biocatalysts Limited Candida lipolitica 96 1 R 24 S 49Lipase AYS Amano Enzyme Inc. Candida rugosa 90 10 S 90 R 50 Lipase L-053Biocatalysts Limited Humicola lanuginosa 2 66 R 1 S 51 Lipase SP523Novozymes Japan Ltd. Humicola sp. 38 63 R 39 S 52 Lipase L-166PBiocatalysts Limited Mucor javanicus 91 4 R 40 S 53 Lipozyme 10000LNovozymes Japan Ltd. Mucor meihei 92 1 R 12 S 54 Lipase SP388 NovozymesJapan Ltd. Mucor miehei 77 11 R 37 S 55 Lipase WO 2-12 BoehringerMannheim GmbH Pseudomonas sp. 6 92 S 6 R 56 Lipase D Amano Enzyme Inc.Rhizopus delemar 82 0 0 57 Lipase L-058 Biocatalysts Limited Rhizopusdelemar 53 5 R 6 S 58 Lipase Saiken 50 Nagase Chemtex CorporationRhizopus javanicus 71 10 R 24 S 59 Lipase Seikagaku Corporation Rhizopusdelemar 68 2 R 4 S 60 Olipase 4S Osaka Saikin Kenkyusho Rhizopusjavanicus 38 20 R 12 S 61 Lipase D Amano Enzyme Inc. Rhizopus delemar 954 R 76 S

ExampleS 62 TO 77 2-Allyloctanoic acid and methyl 2-allyloctanoate

A medium (pH 7.0) comprising 1% of polypeptone, 1% of meat extract, 0.5%of yeast extract and 0.3% of sodium chloride was distributed in 5-mlportions into test tubes and, after sterilization, seeded respectivelywith the microorganisms specified in Table 7. Shake culture wasperformed aerobically at 30° C. for 2 days. Cells were collected fromeach culture fluid by centrifugation and suspended in 1 ml of 500 mMphosphate buffer (pH 7.0). A 5-mg portion of racemic methyl2-allyloctanoate was added to the suspension and, after tight closure,shaking was carried out at 30° C. for 15 hours. After the reaction, thereaction mixture was acidified by addition of 0.25 ml of 3 Mhydrochloric acid and then extracted with 1 ml of ethyl acetate. Theethyl acetate phase was analyzed by gas chromatography, and the degreeof conversion, the optical purity of the product, 2-allyloctanoic acidand the optical purity of the remaining substrate, methyl2-allyloctanoate were determined. The results thus obtained are shown inTable 7. TABLE 7 Optical purity Optical purity of Degree of of theproduct Remaining substrate conversion Absolute Absolute ExampleMicroorganism (%) (% e.e.) configuration (% e.e.) configuration 62Brevundimonas diminuta IFO 13181 14 50 S 8 R 63 Brevundimonas diminutaIFO 13182 13 47 S 7 R 64 Cellulomonas fimi IFO15513 60 46 S 69 R 65Jensenia canicruria IFO 13914 42 96 S 70 R 66 Rhodococcus erythropolisIFO 12320 44 92 S 72 R 67 Rhodococcus erythropolis IFO 12538 30 87 S 38R 68 Rhodococcus erythropolis VIFO 12539 30 85 S 37 R 69 Rhodococcuserythropolis IAM 1474 17 62 S 13 R 70 Rhodococcus erythropolis IFO 1232041 84 S 58 R 71 Rhodococcus erythropolis JCM 3132 33 88 S 44 R 72Rhodococcus erythropolis IAM 1440 36 87 S 49 R 73 Rhodococcuserythropolis IAM 1452 37 84 S 50 R 74 Rhodococcus erythropolis IAM 146336 90 S 51 R 75 Rhodococcus erythropolis IAM 1494 25 66 S 22 R 76Rhodococcus erythropolis IAM 1474 21 67 S 18 R 77 Rhodococcuserythropolis IAM 12122 15 75 S 13 R

ExampleS 78 TO 81 2-Allyloctanoic acid and methyl 2-allyloctanoate

Using the microorganisms listed in Table 8, the procedure of Examples 62to 77 was repeated in the same manner except that a medium (pH 6.5)comprising 2% of malt extract, 2% of glucose, 0.3% of peptone and 0.3%of yeast extract was used, and the degree of conversion, the opticalpurity of the product, 2-allyloctanoic acid and the optical purity ofthe remaining substrate, methyl 2-allyloctanoate were determined in eachrun. The results obtained are shown in Table 8. TABLE 8 Optical purityOptical purity of Degree of of the product Remaining substrateconversion Absolute Absolute Example Microorganism (%) (% e.e.)configuration (% e.e.) configuration 78 Candida pini IFO 1327 30 90 R 39S 79 Saccharomycopsis selenospora IFO 1850 18 82 R 18 S 80 Trichosporoncutaneum IFO 1198 13 71 S 10 R 81 Trichosporon debeurmannianum CBS 189619 94 R 22 S

Example 82 2-Allyloctanoic acid and methyl 2-allyloctanoate

In a flask, there were placed 50 ml of 100 mM phosphate buffer (pH 6.0),6 g of Novozyme CALB L (product of Novozyms) and 2 g of methyl(S)-2-allyloctanoate (60% ee) prepared in Example 31. After tightclosure, the flask was shaken at 40° C. for 77 hours. To the mixture wasadded 0.35 ml of a 55% (w/w) aqueous solution of sulfuric acid, and theresulting mixture was extracted with two 100-ml portions of ethylacetate. The organic phases were combined, and the product wastransferred to 100 ml of a 0.3 M aqueous solution of sodium carbonate.Furthermore, 5 ml of a 55% (w/w) aqueous solution of sulfuric acid wasadded to that aqueous phase, followed by extraction with 50 ml of ethylacetate. The organic phase was washed with 50 ml of water, and thesolvent was then distilled off to give 1.21 g of (S)-2-allyloctanoicacid (99% ee) . The organic phase remaining after the transfer of thereaction product to the 100 ml portion of the 0.3 M aqueous solution ofsodium carbonate was washed with 50 ml of water, and the solvent wasthen distilled off to give 0.63 g of methyl (R)-2-allyloctanoate (14%ee).

INDUSTRIAL APPLICABILITY

As described hereinabove, it is possible to produce an optically active2-allylcarboxylic acid derivative, which is useful as an intermediatefor the manufacture of medicinal compounds, and the like, from readilyavailable and inexpensive starting materials by the process which can bepracticed on a commercial scale in a simple and easy manner.Furthermore, certain 2-allylcarboxamide derivative compounds, which arenovel and important intermediates in that process, can be provided.

1. A 2-allylcarboxamide derivative compound represented by the followingformula (1);

wherein R¹, R² and R⁴ each independently represents a substituted orunsubstituted alkyl group containing 1 to 18 carbon atoms, a substitutedor unsubstituted aryl group containing 6 to 20 carbon atoms or asubstituted or unsubstituted aralkyl group containing 7 to 20 carbonatoms, R³ represents a hydrogen atom, a substituted or unsubstitutedalkyloxycarbonyl group containing 2 to 20 carbon atoms, a substituted orunsubstituted aryloxycarbonyl group containing 7 to 20 carbon atoms or asubstituted or unsubstituted aralkyloxycarbonyl group containing 8 to 20carbon atoms, and *1 and *2 each indicates that the carbon atom markedtherewith is an asymmetric carbon atom.
 2. The compound according toclaim 1, wherein R¹ is a substituted or unsubstituted aryl groupcontaining 6 to 20 carbon atoms.
 3. The compound according to claim 1,wherein R¹ is a group selected from among phenyl group, 4-methylphenylgroup, 4-methoxyphenyl group, 3-methoxyphenyl group, 4-nitrophenylgroup, 4-chlorophenyl group, 4-bromophenyl group, 1-naphthyl group and2-naphthyl group.
 4. The compound according to claim 1, wherein R² is asubstituted or unsubstituted alkyl group containing 1 to 18 carbonatoms.
 5. The compound according to claim 1, wherein R² is methyl group.6. The compound according to claim 1, wherein R³ is a hydrogen atom. 7.The compound according to claim 1, wherein R³ is phenyloxycarbonylgroup.
 8. The compound according to claim 1, wherein R³ isisopropyloxycarbonyl group.
 9. The compound according to claim 1,wherein R⁴ is a substituted or unsubstituted alkyl group containing 1 to18 carbon atoms.
 10. The compound according to claim 1, wherein R⁴ isn-hexyl group.
 11. The compound according to claim 1, wherein theasymmetric carbon atom marked with * 1 has the R-form or S-form absoluteconfiguration.
 12. The compound according to claim 1, wherein theasymmetric carbon atom marked with *2 has the R-form or S-form absoluteconfiguration.
 13. A process for producing an optically active2-allylcarboxylic acid represented by the following formula (5);

wherein R⁴ represents a substituted or unsubstituted alkyl groupcontaining 1 to 18 carbon atoms, a substituted or unsubstituted arylgroup containing 6 to 20 carbon atoms or a substituted or unsubstitutedaralkyl group containing 7 to 20 carbon atoms and *2 indicates that thecarbon atom marked therewith is an asymmetric carbon atom;, whichcomprises: (a) reacting a carboxamide compound represented by thefollowing formula (2);

wherein R¹ and R² each independently represents a substituted orunsubstituted alkyl group containing 1 to 18 carbon atoms, a substitutedor unsubstituted aryl group containing 6 to 20 carbon atoms or asubstituted or unsubstituted aralkyl group containing 7 to 20 carbonatoms, R⁴ is as defined above and * 1 indicates that the carbon atommarked therewith is an asymmetric carbon atom; with an organometalliccompound and then further with a compound represented by the formula;ClCOOR⁵ wherein R⁵ represents a substituted or unsubstituted alkyl groupcontaining 1 to 18 carbon atoms, a substituted or unsubstituted arylgroup containing 6 to 20 carbon atoms or a substituted or unsubstitutedaralkyl group containing 7 to 20 carbon atoms; to give a2-allylcarboxamide derivative represented by the following formula (3);

wherein R¹, R², R⁴, R⁵, *1 and *2 are as defined above;, (b) reactingthe derivative (3) with a compound represented by the formula MOR⁶wherein M represents an alkali metal and R⁶ represents a substituted orunsubstituted alkyl group containing 1 to 20 carbon atoms to give a2-allylcarboxylic acid ester derivative represented by the followingformula (4);

wherein R⁴, R⁶ and *2 are as defined above;, and (c) further hydrolyzingthe derivative (4).
 14. The process according to claim 13, wherein anorganomagnesium compound is used as the organometallic compound.
 15. Theprocess according to claim 14, wherein a tert-butylmagnesium halide isused as the organomagnesium compound.
 16. The process according to claim15, wherein tert-butylmagnesium chloride is used as thetert-butylmagnesium halide.
 17. The process according to claim 13,wherein R⁵ is phenyl group.
 18. The process according to claim 13,wherein R⁵ is isopropyl group.
 19. The process according to claim 13,wherein M is a sodium atom.
 20. The process according to claim 13,wherein R⁶ is methyl group.
 21. The process according to claim 13,wherein the step (b) is carried out in the presence of not less than 1.0mole, per mole of the compound represented by the formula (3), of R⁶OH.22. The process according to claim 13, wherein the compound representedby the formula (2) is in an optically active form.
 23. The processaccording to claim 13, wherein the hydrolysis in step (c) is carried outusing an enzyme source capable of causing asymmetric hydrolysis.
 24. Theprocess according to claim 23, wherein the enzyme source is an enzymesource derived from a microorganism belonging to the genus Candida,Humicola, Mucor, Pseudomonas, Rhizopus, Brevundimonas, Cellulomonas,Jensenia, Rhodococcus, Saccharomycopsis or Trichosporon.
 25. The processaccording to claim 23, wherein the enzyme source is an enzyme sourcederived from Candida antarctica, Candida lipolitica, Candidacylindracea, Candida rugosa, Humicola sp., Humicola lanuginosa, Mucormeihei, Mucor javanicus, Pseudomonas sp., Rhizopus delemar, Rhizopusjavanicus, Brevundimonas diminuta, Cellulomonas fimi, Jenseniacanicruria, Rhodococcus erythropolis, Candida pini, Saccharomycopsisselenospora, Trichosporon cutaneum or Trichosporon debeurmannianum. 26.A process for producing a 2-allylcarboxamide derivative represented bythe following formula (6);

wherein R¹, R² and R⁴ each independently represents a substituted orunsubstituted alkyl group containing 1 to 18 carbon atoms, a substitutedor unsubstituted aryl group containing 6 to 20 carbon atoms or asubstituted or unsubstituted aralkyl group containing 7 to 20 carbonatoms and *1 and *2 each indicates that the carbon atom marked therewithis an asymmetric carbon atom;, which comprises reacting a carboxamidecompound represented by the following formula (2)

wherein R¹, R², R⁴ and *1 are as defined above; with an organometalliccompound.
 27. The process according to claim 26, wherein the compoundrepresented by the formula (2) is in an optically active form.
 28. Theprocess according to claim 26, wherein an organomagnesium compound isused as the organometallic compound.
 29. The process according to claim28, wherein a tert-butylmagnesium halide is used as the organomagnesiumcompound.
 30. The process according to claim 29, whereintert-butylmagnesium chloride is used as the tert-butylmagnesium halide.31. The process according to claim 26, wherein the compound representedby the formula (6) is recrystallized from a solvent to increase thediastereomeric excess thereof.
 32. A process for producing a2-allylcarboxamide derivative represented by the following formula (3);

wherein R¹, R², R⁴ and R⁵ each independently represents a substituted orunsubstituted alkyl group containing 1 to 18 carbon atoms, a substitutedor unsubstituted aryl group containing 6 to 20 carbon atoms or asubstituted or unsubstituted aralkyl group containing 7 to 20 carbonatoms, and *1 and *2 each indicates that the carbon atom markedtherewith is an asymmetric carbon atom; which comprises reacting acompound represented by the following formula (6);

wherein R¹, R², R⁴, *1 and *2 are as defined above; in the presence of abase and further with a compound represented by the formula;ClCOOR⁵ wherein R⁵ is as defined above.
 33. The process according toclaim 32, wherein an alkali metal compound or an alkaline earth metalcompound is used as the base.
 34. The process according to claim 33,wherein sodium hydride is used as the alkali metal compound.
 35. Theprocess according to claim 33, wherein an organomagnesium compound isused as the alkaline earth metal compound.
 36. The process according toclaim 35, wherein a tert-butylmagnesium halide is used as theorganomagnesium compound.
 37. The process according to claim 36, whereintert-butylmagnesium chloride is used as the tert-butylmagnesium halide.38. The process according to claim 32, wherein R⁵ is phenyl group. 39.The process according to claim 32, wherein R⁵ is isopropyl group.
 40. Aprocess for producing a 2-allylcarboxamide derivative represented by thefollowing formula (3);

wherein R¹, R², R⁴ and R⁵ each independently represents a substituted orunsubstituted alkyl group containing 1 to 18 carbon atoms, a substitutedor unsubstituted aryl group containing 6 to 20 carbon atoms or asubstituted or unsubstituted aralkyl group containing 7 to 20 carbonatoms, and *1 and *2 each indicates that the carbon atom markedtherewith is an asymmetric carbon atom; which comprises reacting acarboxamide compound represented by the following formula (2);

wherein R¹, R², R⁴ and *1 are as defined above; with an organometalliccompound and further with a compound represented by the formula;ClCOOR⁵ wherein R⁵ is as defined above.
 41. The process according toclaim 40, wherein an organomagnesium compound is used as theorganometallic compound.
 42. The process according to claim 41, whereina tert-butylmagnesium halide is used as the organomagnesium compound.43. The process according to claim 42, wherein tert-butylmagnesiumchloride is used as the tert-butylmagnesium halide.
 44. The processaccording to claim 40, wherein R⁵ is phenyl group.
 45. The processaccording to claim 40, wherein R⁵ is isopropyl group.
 46. A process forproducing a 2-allylcarboxylic acid represented by the following formula(8);

wherein R⁴ represents a substituted or unsubstituted alkyl groupcontaining 1 to 18 carbon atoms, a substituted or unsubstituted arylgroup containing 6 to 20 carbon atoms or a substituted or unsubstitutedaralkyl group containing 7 to 20 carbon atoms, R⁹ represents a hydrogenatom or a substituted or unsubstituted alkyl group containing 1 to 20carbon atoms, and * indicates that the carbon atom marked therewith isan asymmetric carbon atom or an ester derivative thereof;, whichcomprises reacting a 2-allylcarboxamide derivative represented by thefollowing formula (7);

wherein R⁴ is as defined hereinabove, R⁷ and R⁸ each represents asubstituted or unsubstituted alkyl group containing 1 to 18 carbonatoms, a substituted or unsubstituted aryl group containing 6 to 20carbon atoms or a substituted or unsubstituted aralkyl group containing7 to 20 carbon atoms and R⁷ and R⁸ may be bound together to form a ring,X represents C, S or S(O), Y represents CH, O or NH and * is as definedhereinabove; with a compound represented by the formula MOR⁹ wherein Mrepresents an alkali metal and R⁹ is as defined hereinabove and, ifnecessary, hydrolyzing the resulting ester.
 47. The process according toclaim 46, wherein M is a sodium atom.
 48. The process according to claim46, wherein R⁹ is methyl group.
 49. A process for producing an opticallyactive 2-allylcarboxylic acid represented by the following formula (5);

wherein R⁴ represents a substituted or unsubstituted alkyl groupcontaining 1 to 18 carbon atoms, a substituted or unsubstituted arylgroup containing 6 to 20 carbon atoms or a substituted or unsubstitutedaralkyl group containing 7 to 20 carbon atoms, and *2 indicates that thecarbon atom marked therewith is an asymmetric carbon atom; whichcomprises causing an enzyme source having asymmetric hydrolysis activityto act on a 2-allylcarboxylic acid ester derivative represented by thefollowing formula (4);

wherein R⁴ is as defined hereinabove, R⁶ represents a substituted orunsubstituted alkyl group containing 1 to 20 carbon atoms, and *2 is asdefined hereinabove; and collecting the resulting optically active2-allylcarboxylic acid.
 50. The process according to claim 49, whereinthe compound represented by the formula (4) is in a racemic form. 51.The process according to claim 49, wherein the compound represented bythe formula (4) is in an optically active form.
 52. A process forproducing an optically active 2-allylcarboxylic acid ester representedby the following formula (4);

wherein R⁴ represents a substituted or unsubstituted alkyl groupcontaining 1 to 18 carbon atoms, a substituted or unsubstituted arylgroup containing 6 to 20 carbon atoms or a substituted or unsubstitutedaralkyl group containing 7 to 20 carbon atoms, R⁶ represents asubstituted or unsubstituted alkyl group containing 1 to 20 carbonatoms, and *2 indicates that the carbon atom marked therewith is anasymmetric carbon atom; which comprises causing an enzyme source havingasymmetric hydrolysis activity to act on a 2-allylcarboxylic acid esterderivative represented by the formula (4) given above and collecting theunreacted optically active 2-allylcarboxylic acid ester.
 53. The processaccording to claim 52, wherein the compound represented by the formula(4) is in a racemic form.
 54. The process according to claim 52, whereinthe compound represented by the formula (4) is in an optically activeform.
 55. The process according to claim 49, wherein R⁶ is methyl groupor ethyl group.
 56. The process according to claim 49, wherein theenzyme is an enzyme source derived from a microorganism belonging to thegenus Candida, Humicola, Mucor, Pseudomonas, Rhizopus, Brevundimonas,Cellulomonas, Jensenia, Rhodococcus, Saccharomycopsis or Trichosporon.57. The process according to claim 49, wherein the enzyme source is anenzyme source derived from Candida antarctica, Candida lipolitica,Candida cylindracea, Candida rugosa, Humicola sp., Humicola lanuginosa,Mucor meihei, Mucor javanicus, Pseudomonas sp., Rhizopus delemar,Rhizopus javanicus, Brevundimonas diminuta, Cellulomonas fimi, Jenseniacanicruria, Rhodococcus erythropolis, Candida pini, Saccharomycopsisselenospora, Trichosporon cutaneum or Trichosporon debeurmannianum.